Psychiatry 2008; 165:1316-1325
Psychiatry 2008; 165:1316-1325(published online April 1, 2008;
doi: 10.1176/appi.ajp.2008.07101560) 2008 American Psychiatric
Association
Efficacy of Adjunctive Aripiprazole to Either Valproate or
Lithium in Bipolar Mania Patients Partially Nonresponsive to
Valproate/Lithium Monotherapy: A Placebo-Controlled Study
Eduard Vieta, M.D., Ph.D., Caroline Tjoen, M.S., Robert D.
McQuade, Ph.D., William H. Carson Jr., M.D., Ronald N. Marcus,
M.D., Raymond Sanchez, M.D., Randall Owen, M.D., and Laurence
Nameche, M.S., M.B.A. Abstract
OBJECTIVE: The authors evaluated the efficacy and safety of
adjunctive aripiprazole in bipolar I patients with mania partially
nonresponsive to lithium/valproate monotherapy. METHOD: This
multicenter, randomized, placebo-controlled study included
outpatients experiencing a manic or mixed episode (with or without
psychotic features). Patients with partial nonresponse to
lithium/valproate monotherapy (defined as a Young Mania Rating
Scale total score 16 at the end of phases 1 and 2, with a decrease
of 25% between phases) with target serum concentrations of lithium
(0.61.0 mmol/liter) or valproate (50125 g/ml) were randomly
assigned in a 2:1 ratio to adjunctive aripiprazole (N=253; 15 or 30
mg/day) or placebo (N=131) for 6 weeks. RESULTS: Mean improvement
from baseline in Young Mania Rating Scale total score at week 6
(primary endpoint) was significantly greater with aripiprazole
(13.3) than with placebo (10.7). Significant improvements in Young
Mania Rating Scale total score with aripiprazole versus placebo
occurred from week 1 onward. In addition, the mean improvement in
Clinical Global Impression Bipolar Version (CGI-BP) severity of
illness (mania) score from baseline to week 6 was significantly
greater with aripiprazole (1.9) than with placebo (1.6).
Discontinuation rates due to adverse events were higher with
aripiprazole than with placebo (9% versus 5%, respectively).
Akathisia was the most frequently reported extrapyramidal
symptom-related adverse event and occurred significantly more
frequently among those receiving aripiprazole (18.6%) than among
those receiving placebo (5.4%). There were no significant
differences between treatments in weight change from baseline to
week 6 (+0.55 kg and +0.23 kg for aripiprazole and placebo,
respectively; last observation carried forward). CONCLUSIONS:
Adjunctive aripiprazole therapy showed significant improvements in
mania symptoms as early as week 1 and demonstrated a tolerability
profile similar to that of monotherapy studies. Introduction
Mood stabilizers in combination with atypical antipsychotics are
a first-line treatment approach for severe manic or mixed bipolar
episodes (13). For mildly ill patients with bipolar disorder,
combination therapies are generally a second-line approach (1), but
mood stabilizer and antipsychotic combinations are widely used (1,
4). The efficacy of such regimens has been demonstrated in several
randomized, controlled studies (510); however, some studies failed
to separate the primary efficacy parameters from placebo (57) and
most did not prospectively ensure patient partial nonresponse using
well-defined rigorous criteria. Studies have shown that the
atypical antipsychotic aripiprazole is effective and well tolerated
in the treatment of acute bipolar mania (11, 12), and it has shown
superiority to haloperidol in response rates and tolerability in a
12-week acute mania trial (13). Furthermore, aripiprazole
monotherapy was superior to placebo in maintaining efficacy in
patients with a recent manic/mixed episode who were stabilized and
maintained on a regimen of aripiprazole for at least 6 weeks (14,
15). However, in a fixed-dose study of aripiprazole in the
treatment of acute mania, aripiprazole did not separate from
placebo despite similar symptom improvements to those seen in other
studies (Otsuka America Pharmaceutical, Inc., unpublished 2003
data), and aripiprazole monotherapy did not demonstrate superior
efficacy to placebo at endpoint in two studies in bipolar
depression (16). The present study is the first randomized,
controlled study to investigate the efficacy and safety of
adjunctive aripiprazole and either lithium or valproate compared
with lithium or valproate plus placebo for the treatment of
patients with bipolar I mania who were partially nonresponsive to
lithium/valproate monotherapy. Method
PatientsEligible patients were ages 18 years or older with
DSM-IV criteria for bipolar I disorder, manic or mixed type (with
or without psychotic features); diagnosis was confirmed by the Mini
International Neuropsychiatric Interview. Patients had a history of
at least one previous manic or mixed episode that required
hospitalization and/or treatment with a mood stabilizer or
antipsychotic. Exclusion criteria were hospitalization for current
manic or mixed episode for more than 3 weeks; previous nonresponse
to treatments for manic symptoms; diagnosis of bipolar II disorder
or rapid cycling bipolar disorder; history of substance abuse or
dependence; significant risk of committing suicide; recent
treatment with a long-acting antipsychotic; or known sensitivity to
any of the study drugs. All patients provided written informed
consent. Study Design and Treatments
Phase 1 was a screening period (328 days, with an extension to
42 days with permission) during which medications other than
lithium or valproate were discontinued. For patients not currently
receiving a mood stabilizer, the investigators determined which
medication to initiate. Patients were required to have a
therapeutic serum level of lithium (0.61.0 mmol/liter) or valproate
(50125 g/ml) and a Young Mania Rating Scale total score 16 at the
end of screening. Median duration of treatment with
lithium/valproate in phase 1 was 16 days (range=369 days) in the
placebo group and 16 days (range=176 days) in the aripiprazole
group. Phase 2 was a 2-week baseline period during which patients
continued to receive open-label lithium or valproate monotherapy.
At week 2, patients with confirmed partial nonresponse (defined as
a Young Mania Rating Scale total score 16 during phase 1 and at the
end of phase 2, with a decrease of 25% between phases) were
randomly assigned in a 2:1 ratio to receive either adjunctive
aripiprazole (15 mg/day) or adjunctive placebo during the 6-week,
double-blind phase (phase 3), stratified by type of mood
stabilizer. Aripiprazole dose could be adjusted after week 1 (to 30
mg/day) based on tolerability or clinical response. During baseline
mood stabilizer treatment (phase 2), lorazepam (4 mg/day) or
equivalents were permitted during week 1 and week 2 (3 mg/day).
Propranolol (maximum dose of 20 mg t.i.d.) was also permitted.
During double-blind treatment (phase 3), patients were permitted
the use of benzodiazepines (2 mg/day of lorazepam or equivalents)
for a maximum of 10 days during the first 4 weeks only.
Anticholinergic therapy (benztropine mesylate or equivalents, 2
mg/day) and propranolol (maximum dose of 20 mg t.i.d., not to be
taken within 8 hours of efficacy or safety assessment) were
permitted for extrapyramidal symptoms. Propranolol for the
treatment of heart disease was also permitted among those patients
receiving it prior to enrollment. AssessmentsDuring double-blind
treatment, efficacy was assessed at day 4 and thereafter at weekly
intervals until week 6. The primary efficacy measure was the mean
change from baseline to week 6 in Young Mania Rating Scale total
score (last observation carried forward). The key secondary measure
was the mean change from baseline to week 6 in Clinical Global
Impression Bipolar Version (CGI-BP) severity of illness (mania)
score. Other secondary measures at week 6 included rates of
response (proportion of patients demonstrating 50% improvement from
baseline in Young Mania Rating Scale total score) and remission
(proportion of patients achieving Young Mania Rating Scale total
score 12); mean change from preceding phase in CGI-BP scores
(mania, depression, and overall); mean change from baseline in
CGI-BP severity of illness (overall) score and (depression) score;
mean change from baseline in Positive and Negative Syndrome Scale
(PANSS) total score and PANSS positive, negative, cognitive, and
hostility subscale scores; mean change from baseline in
Montgomery-sberg Depression Rating Scale (MADRS) total score;
proportion of patients with emergent depression (defined as a MADRS
total score 18 plus a 4-point increase from baseline in any two
consecutive assessments); and time from random assignment to
response and remission. A priori analyses were also performed on
subgroups of patients receiving lithium or valproate. A post-hoc
analysis was conducted to evaluate remission using criteria from
both illness poles (proportion of patients achieving Young Mania
Rating Scale total score 12 plus a MADRS total score 8). Mean
change from baseline to week 6 in Longitudinal Interval Follow-Up
EvaluationRange of Impaired Function Tool total score was also
evaluated. Safety evaluations were based on reports of adverse
events, vital signs, electrocardiogram (ECG) findings, and weight
and laboratory assessments. Severity of extrapyramidal symptoms was
assessed using the Simpson-Angus Scale, the Barnes Rating Scale for
Drug-Induced Akathisia, and the Abnormal Involuntary Movement Scale
(AIMS). Statistical Analyses
A sample size of 360 (aripiprazole: N=240; placebo: N=120) was
chosen to provide 90% power to detect a difference of 3.2 points in
the mean change from baseline to week 6 in Young Mania Rating Scale
total score between adjunctive aripiprazole and adjunctive placebo.
Analyses were performed on both the last observation carried
forward and the observed data. Continuous efficacy measures were
evaluated using analysis of covariance (ANCOVA) and adjusted for
treatment, baseline measurement, and type of mood stabilizer. A
hierarchical testing procedure was used to preserve the
significance level at 0.05. If the difference between aripiprazole
and placebo on the primary efficacy measure was statistically
significant (p0.05), then testing of the difference between
aripiprazole and placebo on the key secondary efficacy measure
could proceed at =0.05. Testing of all other secondary endpoints
was performed at the =0.05 significance level without adjustment
for multiple comparisons and multiple testing. Binary outcomes were
analyzed using Cochran-Mantel-Haenszel general association
statistics stratified by type of mood stabilizer. All tests were
two-sided. Time from random assignment to response and remission
were evaluated by survival analyses and Kaplan-Meier survival
curves. Log-rank tests stratified by type of mood stabilizer were
used to compare survival distributions between treatment groups.
Parameter estimates and 95% confidence intervals (CI) for the
hazard ratio were obtained using a Cox regression model with
treatment as a covariate, stratified by type of mood stabilizer.
Post-hoc analyses were conducted to calculate an effect size (d)
using the Cohen method for paired samples (17) minus the difference
in mean change in Young Mania Rating Scale total score between the
placebo and the aripiprazole group, divided by the pooled standard
deviation (SD). The number needed to treat, or the average number
of patients who needed to be treated to show response in one
additional patient, was also calculated. Post-hoc analysis of the
change from baseline across all 11 items of the Young Mania Rating
Scale was also conducted. Results
Patient Characteristics and Disposition
The progress of patients through the trial is shown in Figure 1.
In total, 384 patients completed the screening and baseline phase
and were randomly assigned to double-blind treatment with either
placebo (N=131) or aripiprazole (N=253). Of the patients who
discontinued the study during the baseline phase (N=54), 21 did so
because they achieved response with lithium/valproate monotherapy
(and thus could not meet criteria for study continuation).
Double-blind treatment was completed by 85% and 79% of patients
randomly assigned to placebo and aripiprazole, respectively.
Discontinuation rates due to adverse events were higher for
patients in the aripiprazole group than for patients in the placebo
group (9% versus 5%; p=0.200). Baseline demographic and clinical
characteristics of patients were similar between treatment groups
(Table 1). [in this window] HYPERLINK
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Figure 1. CONSORT Diagram
aOne patient received double-blind study medication during phase
2 in error.
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TABLE 1
Study Treatments
Of the patients randomly assigned to double-blind treatment
(N=384), 157 were receiving lithium and 227 were receiving
valproate. For the patients assigned to adjunctive aripiprazole,
the mean dose of aripiprazole during week 6 was 19.0 mg/day. For
the lithium subgroup, the mean dose of lithium the day before
starting adjunctive treatment was 994 mg/day and 1,119 mg/day for
the placebo and aripiprazole arms, respectively. Mean lithium serum
levels at baseline in these two groups were 0.77 mmol/liter
(SD=0.17) and 0.78 mmol/liter (SD=0.22), respectively. The mean
dose of lithium during week 6 of double-blind treatment was 985
mg/day and 1,160 mg/day for the placebo and aripiprazole groups,
respectively. Mean lithium serum levels at week 6 (last observation
carried forward) were similar in both groups (placebo: 0.72
mmol/liter [SD=0.22]; aripiprazole: 0.76 mmol/liter [SD=0.35]; t=
0.87, df=140, p=0.385). A similar proportion of patients in both
arms had a serum lithium level within the therapeutic range at
endpoint (placebo: 68.0%; aripiprazole: 69.9%). For the valproate
subgroup, the mean dose the day before starting adjunctive
treatment was 1,175 mg/day and 1,180 mg/day for the placebo and
aripiprazole arms, respectively. The mean serum valproate level at
baseline in the two groups was 77.2 g/ml (SD=23.4) and 77.8 g/ml
(SD=21.0), respectively. The mean dose of valproate during week 6
of double-blind treatment was 1,179 mg/day and 1,225 mg/day for the
placebo and aripiprazole groups, respectively. Similar mean serum
valproate levels at endpoint (week 6; last observation carried
forward) were seen between the two groups (placebo: 68.35 g/ml
[SD=23.92]; aripiprazole: 68.23 g/ml [SD=23.63]; t=0.04, df=161,
p=0.971). A similar proportion of patients in both arms had a serum
valproate level within the therapeutic range at endpoint (placebo:
78.8%; aripiprazole: 80.0%). More than 40% of patients received
concomitant CNS medication. The most frequently taken CNS
medications were anxiolytics (placebo: 24.6%; aripiprazole: 20.9%)
and other analgesics and antipyretics (placebo: 23.1%;
aripiprazole: 21.3%). A total of 47 (18.6%) patients in the
aripiprazole group received a concomitant medication for the
potential treatment of extrapyramidal symptoms, compared with nine
(6.9%) patients in the placebo group. EfficacyAt week 6, adjunctive
aripiprazole showed significantly greater improvements from
baseline in Young Mania Rating Scale total score than placebo (13.3
[SD=7.9] versus 10.7 [SD=7.6]; F=9.54, df=1, 373, p
